Abstract C59: Variable distribution of HIF-1α in human normal and carcinoma tissue, immortal cell lines, and effects of hyperoxia / hypoxia on HIF-1α deficient cells

Abstract

Abstract Inadequate access to healthcare can lead to greater mortality rates from a delay in cancer diagnosis. It is believe that over time, the hypoxic microenvironment of solid tumors can elicit an elevation of HIF-1α, its translocation to the nucleus and targeted effects on the hypoxic response element (HRE) - initiating invasive metastasis. While this is a universally held supposition, “HIF-1α negative tumors” can also display aggressive pathology and poor clinical outcome. Given inconsistencies in the literature, we analyze public data sets for baseline HIF-1α gene expression amongst 329 human tissues (168 cancer, 161 normal) and NCI60 tumor cell lines. The data show little to no differences between a number of tumor and normal tissue samples, with some exceptions such as the case of bronchial epithelial tissue, exacerbated in respective cancer tissue. The data show extreme variation in HIF-1α across individuals with similar human cancers (below L.O.D. - 60% of GAPDH) with comparable patterns across tissue specific immortal cell lines (1% - 70% of GAPDH). Moreover, the effects of hyperoxia ∼91% O2, hypoxia ∼2.5% O2 versus normoxia ∼21% CO2/ 5% CO2/atm on a HIF-1α deficient malignant neuroblastoma cell line (N2a) were explored using Agilent genomic 4 x 44 k arrays. Hyperoxia evoked a rise in mRNA for 42 mitochondrial OXPHOS genes, DNA/base excision repair, protein synthesis, transcription, cytoskeletal proteins, G-protein signaling and ubiquitin-mediated proteolysis. On the other hand, hypoxia triggered primarily upregulation of chromatin remodeling events such as LDS's, histone-clusters H4k/d/j, Hist4h4, Hist2h3c1, Rara and REST co-repressor. In HIF-1α deficient tumor cells, a decline in O2 initiates epigenetic changes that parallel elevation of VEGF and ubiquitin proteolysis, albeit not related to HIF-1 α. Future research will be required to corroborate similar findings in other HIF-1α deficient models. Citation Format: Elizabeth Mazzio, Karam FA Soliman. Variable distribution of HIF-1α in human normal and carcinoma tissue, immortal cell lines, and effects of hyperoxia / hypoxia on HIF-1α deficient cells. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C59. doi:10.1158/1538-7755.DISP13-C59